New and Noteworthy in Tuberculosis Diagnostics and Treatment
New and Noteworthy in Tuberculosis Diagnostics and Treatment Susan Swindells, MBBS Professor of Internal Medicine University of Nebraska Medical Center Omaha, Nebraska From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA. San Antonio, Texas: August 21 to 23, 2017
Learning Objectives After attending this presentation, learners will be able to: �Describe the diagnosis and treatment of latent tuberculosis infection �Identify new developments in diagnostics for TB disease �Apply in practice the current guidelines for HIV/TB co-treatment Slide. S 2 of XX MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA. From Swindells, Slide 2 of 36
Slide 3 of 36 TB is a Major Global Health Problem 23% world population Infected with TB 1 In 2015: 2 10 m new cases 1. 2 m had HIV 1. 4 m deaths 0. 4 m with HIV > 1000/day 1. Houben Plos. Med 2016; 2. WHO report From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Slide 4 of 36 Case #1 n n n A 34 -year-old man establishes care in your clinic Born in Mexico, he emigrated to the US 6 years ago HIV diagnosed 6 months ago during admission for community acquired pneumonia HIV now well controlled on TAF/FTC/elvitegravir/cobi/ (Genvoya) Last CD 4 120, VL < 40 You test him for latent TB with an IGRA (in this case, quanti. FERON), result is “indeterminate” From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Slide 5 of 36 Recommendations for LTBI testing in HIV n n n n Risk of progression to TB disease 10 x greater in HIV+ CDC recommends testing after HIV diagnosis and then annually if negative or if exposure risk If pre-ART negative, repeat after ART initiation No direct test for LTBI, can use TST or IGRA Neither test predicts risk of progression to active TB No benefit to repeating either test once positive LTBI testing should not be used to diagnose active TB http: //www. cdc. gov/tb/publications/ltbi/diagnosis. htm From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Slide 6 of 36 TB Skin Test Induces DTH response if pt infected Interferon –Gamma release Assay Measures immune response to TB in whole blood 2 to 7 days later ≥ 5 mm positive in HIV+ pts From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
TST/IGRA Comparison Both tests ~65 -70% sensitive in HIV+ TST IGRA n n Requires 2 visits Interpretation same if pt had BCG vaccine n n n n Result will be negative or positive in mm induration Requires training to administer and interpret Testing for anergy not recommended Cheaper than IGRA n n Single visit Unaffected by BCG Result can be positive, negative or indeterminate Indeterminate more common with immunosuppression (CD 4 <200) Blood must be processed in 8 -30 h Limited data in small children, recent TB exposure From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA. Slide 7 of 36
Slide 8 of 36 Case #1 continued n n n After 6 months treatment with TAF/FTC/elvitegravir/cobi, CD 4 count is 300 Repeat IGRA is positive Patient has no signs or symptoms of active TB and has a normal chest x-ray From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Slide 9 of 36 CDC Recommendations for LTBI Treatment in HIV-infected Patients n INH daily or twice weekly for 9 months INH + rifapentine weekly for 12 weeks Rifampin (or rifabutin) daily for 4 months n Monitor patients monthly for hepatitis and other side effects n n http: //www. cdc. gov/tb/topic/treatment/ltbi. htm From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Slide 10 of 36 Beware Drug-Drug Interactions From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
RIFAMPIN: A potent inducer of metabolizing enzymes Slide 11 of 36 This complicates co-treatment of TB and other diseases tremendously RIF PXR Cytoplasm RIF PXR RXR CYP 3 A 4 proximal promoter CYP 3 A 4 XRE Phase II enzyme regulatory genes RXR PGP regulatory gene MDR 1 protein regulatory gene DNA m. RNA Nucleus Dooley et al. (2008) JID 198: 948. From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Slide 12 of 36 LTBI/HIV Treatment Considerations n n Any ART regimen can be used when isoniazid alone is used for LTBI treatment Only efavirenz or raltegravir based regimens can be used with once-weekly isoniazid plus rifapentine • NOTE: TAF contraindicated n Check carefully for DDI with rifamycins • Can use EFV or double dose DTG with rifampin • Can use PI with rifabutin at 150 mg daily or 300 mg 3 times a week https: //aidsinfo. nih. gov/contentfiles/lvguidelines/adultandadolescentgl. pdf http: //www. hiv-druginteractions. org/ Both have free apps From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Efficacy of IPT in HIV+ Adults: Risk of TB • 11 randomized trials with 8, 130 HIV+ participants overall reduction in TB = 36%, reduction PPD+ = 62% Woldehanna and Volmink, Cochrane Review 2006 From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA. Slide 13 of 36
Slide 14 of 36 Slide 14 of 39 Early ART Prevents TB: The Temprano Trial n n n 2056 patients with CD 4 <800 randomized to immediate or deferred ART +/- IPT 42% endpoints = TB ART and IPT decreased risk of TB independently From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA. NEJM 2015
Slide 15 of 36 Case #2 54 -year-old woman is admitted to your hospital with cough, fever, and weight loss n n Diagnosed with HIV on admission, CD 4+ 70, HIV RNA 120 K n CXR shows pleural thickening and diffuse infiltrate n Sputum AFB smear negative, bronch negative for PCP From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Slide 16 of 36 How To Diagnose or Exclude TB: Novel Diagnostics Now Available Xpert MTB/RIF: 2 hour molecular test for M. TB diagnosis and rifampin resistance (1) More sensitive than AFB smear Works in children and extrapulmonary TB Screen for MDR and XDRTB Xpert Ultra in development (2) TB Diagnostic for 2 Centuries Genotype MTBDR plus • Diagnosis in 5 hours • Identifies RIF and INH resistance 1. Lawn, Lancet ID, 2013 ; 2. Alland, CROI 2015 From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Slide 17 of 36 Detection: Sensitivity TBTBDetection: Sensitiv CID 2016: 62 (1 May) N=992, 45% HIV+, median CD 4 151 Sensitivity (95% CI) Xpert +/ TB culture + Overall 85. 8% (78. 0, 91. 2%) 91/106 AFB+/TB culture + 100% ( 94. 6, 100%) 67/67 AFB-/TB culture + 61. 5% (45. 9, 75. 1%) 24/39 From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
TB Detection: Specificity Slide 18 of 36 Specificity (95% CI) Xpert -/ TB culture Overall 98. 9% (97. 6, 99. 4%) 591/598 AFB+/TB culture + 100% (51. 0, 100 %) 4/4 AFB-/TB culture + 98. 8% (97. 6, 99. 4%) 587/594 US only AFB+/TB culture + AFB-/TB culture + 99. 3% (98. 0%, 99. 8%) 441/444 100% (51%, 100%) 4/4 99. 3% (98. 0%, 99. 8%) Xpert now FDA approved for use in TB infection control 437/440 Can take pt out of isolation after 1 or 2 negative tests http: //www. fda. gov/News. Events/Newsroom/Press. Announcements/ucm 434226. htm From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Slide 19 of 36 Case #2 Continued n n n Your pt is diagnosed with TB by Xpert MTB/RIF with culture pending Started on treatment for TB with isoniazid, rifampin, ethambutol and pyrazinamide When should you start ART? From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Treatment strategy of immediate TB therapy + early ART (2 vs 8 weeks) saves lives and reduces HIV complications CAMELIA (Cambodia) SAPIT (South Africa) STRIDE (multicontinent) From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA. Slide 20 of 36
Slide 21 of 36 Early ART improves survival, no increased risk of AE but some increase in IRIS From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Slide 22 of 36 Current Guidelines n n n WHO, ATS and DHHS guidelines all recommend: Initiation of ART within 2 weeks for CD 4 count <50 Initiation of ART within 8 weeks for CD 4 >50 • Exception for TB meningitis where increased AE and death reported with early ART in a randomized trial [Torok CID 2011] From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Slide 23 of 36 HIV/TB co-treatment options for adults ARV* Rifamycin Dose adjustments Preferred Efavirenz Rifampin None Lopinavir/ Rifabutin 150 mg once daily Ritonavir (Darunavir/r) Alternative Raltegravir Rifampin Raltegravir 400 or 800 mg twice daily Other Issues Watch for CNS toxicity Monitor for uveitis; Must coordinate care Limited clinical experience Dolutegravir Rifampin Dolutegravir 50 mg twice daily Awaiting results of trial in co-infected patients Nevirapine Avoid NVP lead-in Hepatotoxicity Rifampin *All listed antiretroviral drugs should be given together with two NRTI but not with TAF From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Slide 24 of 36 Do Not Use Rifamycins With TAF • TDF has been studied with RIF without significant interaction 1 • TAF contraindicated with rifamycins in all package inserts • Based on modeling data with carbamazepine – Carbamazepine reduced TAF exposure 55% • TAF more influenced by P-Glycoprotein induction than TDF – (P-GP = protein that pumps foreign substances out of cells) 1 Droste JAH, et al. Antimicrob Agents Chemother 2005 From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Slide 25 of 36 Why Not Just Use Rifabutin? n Cochrane review: “insufficient data to be assured of the effectiveness of rifabutin in TB treatment” 1 – Clinical trials comparing RBT to RIF were largely conducted among patients not on ART n Correct dose uncertain • Most PK studies done in healthy volunteers; some data to suggest 300 mg tiw insufficient in HIV+ pts n n n Risk of uveitis Expensive No pediatric formulation 1 Davies GR, Cerri S, Richeldi L. Rifabutin for treating pulmonary tuberculosis (Review). In: The Cochrane Library, John Wiley & Sons, Ltd. , 2010 From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Use of EFAVIRENZ with TB treatment Food and Drug Administration - January 6, 2012 “If Sustiva is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of Sustiva to 800 mg once daily is recommended. ” From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA. Slide 26 of 36
What is the right dose of EFAVIRENZ with TB treatment? Slide 27 of 36 (do we need a dose adjustment? ) EFV with RIF EFV alone ACTG Trial A 5221 EFV PK Substudy, N= 543 RIF PK TB-Rx No TB-Rx Cmin (ng/m. L)* 1. 96 (1. 24 -3. 79) 1. 80 (1. 26 -2. 63) *Median (IQR) Luetkemeyer et al. Clinical Infectious Diseases (2013) 57: 586. From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Case #3 continued n Your patient with TB starts ART after weeks 10 days later, she has recurrent fever Worsening dyspnea and cough A CXR shows progression of the pulmonary infiltrates n You suspect Immune Reconstitution Inflammatory Syndrome (IRIS) n n n From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA. Slide 28 28 of of 36 36
Immune Reconstitution Disease • • More common with early ART More common with low CD 4 count Rarely severe or fatal Management: – Make certain of diagnosis – Rule out MDR TB or new OI – Surgical drainage – Non-steroidal anti-inflammatory drugs • Quality of evidence low – Prednisone • 1. 5 mg/kg per day for 2 weeks then 0. 75 mg/kg per day for 2 weeks reduces risk of adverse events (Meintjes, AIDS 2010) From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA. Slide 29 of 36
Slide 30 of 36 Summary: Barriers to Overcome n n No “viral load” test for TB Treatment shortening not successful so far Better treatment for children needed Some TB agents in development interact with ART and some are stalled From S Swindells, MBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA.
Conclusions �TB can be prevented by treating HIV and/or by treating LTBI �Major improvements in TB diagnostics �Not enough new drugs �TB and HIV should be treated concurrently �Drug-drug interactions complicate HIV co-treatment, but �Safe and effective regimens for TB and HIV co-treatment are available �We need more research investment and advocacy Slide. S 31 of XXMBBS at San Antonio, Texas, August 21 -23, 2017, Ryan White HIV/AIDS Program Clinical Conference, IAS USA. From Swindells, Slide 31 of 36
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